One possibility of great clinical significance is that the albuterol non-responders have genetically determined differences in β2AR that down regulate effectiveness. Various polymorphisms have been described in this receptor with the greatest attention being devoted to single nucleotide polymorphisms (SNPs) substitutions at amino acid positions 16 (arginine to glycine, Arg 16 Gly) and 27 (glutamine to glutamic acid, Gln 27 Glu). The Gly 16 receptor exhibits enhanced down regulation in vitro after exposure to agonist while the Arg 16 allele is more resistant. The Gly 16 allele is strongly associated with asthma destabilizations as manifested by nocturnal symptom and an increased risk of severity. In contrast, Arg/Arg homozygosity at position 16 has been associated with poorer outcomes in prospective studies of regular use of short-acting β2 agonists. This phenomenon was not seen in asthmatics that used albuterol on an as needed basis or those who were homozygous for glycine. Since over 90 % of the subjects in our studies, and those of others, on acute asthma take this drug routinely and the vast majority are treated with it emergently, the presence of the Arg/Arg allele could lead to poorer responses. It has also been suggested that this polymorphism may also produce similar effects with long-acting β2 agonists. Again, since a large percentage of asthmatic patients chronically use long acting sympathomimetics, this factor may have a contributory effect. Alternatively, β2AR pharmacogenetics may be totally unimportant. Two studies have implied that neither single genotypes at Codon 16, nor haplotypes in the β2AR have any effect on the acute bronchodilator response to either albuterol or salbutamol. However, since these trials were performed in stable patients, they may not be representative of the non-responsive group described above.